Shaughnessy John
Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Hematology. 2005;10 Suppl 1:117-26. doi: 10.1080/10245330512331390140.
The molecular basis for aggressive transformation of multiple myeloma (MM) and other cancers is not completely understood. Global gene expression profiling on highly purified malignant plasma cells from 351 newly diagnosed patients with MM treated with autologous stem cell transplantation revealed a statistically significant over-representation of chromosome 1 genes in a group of 70 genes whose expression was linked to poor outcome. In particular, over-expression of CKS1B, which maps to an amplicon at 1q21 in myeloma and regulates SCF(Skp2)-mediated ubquitination and proteolysis of the cyclin dependent kinase inhibitor p27Kip1 was significantly over-expressed in patients with poor survival. Interphase fluorescence in-situ hybridization revealed that CKS1B expression was strongly correlated with DNA copy number in a subset of 197 cases (P<0.0001) with both measurements. Validated in 224 patients lacking expression analysis, CKS1B gene amplification conferred a poor prognosis (P<0.0001) and was an independent predictor of outcome in multivariate analyses (P=0.002). CKS1B mRNA and protein expression were correlated and both were inversely correlated with p27(Kip1) protein levels. RNA interference of CKS1B messenger RNA in myeloma cell lines led to reduced CKS1B mRNA and protein, an accumulation of p27Kip1, and profound growth inhibition. Based on these data we conclude that over-expression of CKS1B, mainly due to gene amplification, imparts a poor prognosis in MM, possibly as a result of enhanced degradation of p27Kip1.
多发性骨髓瘤（MM）及其他癌症侵袭性转化的分子基础尚未完全明确。对351例接受自体干细胞移植治疗的新诊断MM患者的高度纯化恶性浆细胞进行全基因组表达谱分析，结果显示，在一组70个与预后不良相关的基因中，1号染色体基因在统计学上显著富集。特别是，定位于骨髓瘤1q21扩增子的CKS1B过表达，其可调节SCF（Skp2）介导的细胞周期蛋白依赖性激酶抑制剂p27Kip1的泛素化和蛋白水解，在生存较差的患者中显著过表达。间期荧光原位杂交显示，在197例同时进行这两项检测的病例子集中，CKS1B表达与DNA拷贝数密切相关（P<0.0001）。在224例未进行表达分析的患者中得到验证，CKS1B基因扩增预示预后不良（P<0.0001），并且在多变量分析中是预后的独立预测因子（P=0.002）。CKS1B mRNA和蛋白表达相关，且均与p27（Kip1）蛋白水平呈负相关。骨髓瘤细胞系中CKS1B信使RNA的RNA干扰导致CKS1B mRNA和蛋白水平降低、p27Kip1积累以及显著的生长抑制。基于这些数据，我们得出结论，CKS1B的过表达（主要由于基因扩增）导致MM预后不良，可能是p27Kip1降解增强的结果。
